The present invention is directed to derivatives of campothecin, preferably having low toxicity, and to the use of these derivatives for cancer treatment. The disclosures of all documents referred to in this application are incorporated herein in whole by reference.
Camptothecin, a cyctotoxic alkaloid first isolated from the wood and bark of Camptotheca Acuminata (Nyssacea) by Wall and his coworkers (J. Am. Chem. Soc. 88, 3888, 1966), was shown to have antitumor activity against the mouse leukemia L 1210 system. The structure of camptothecin, an alkaloid which has a commonly occurring indole alkaloid group (Heckendorf et al. J Org. Chem. 41, 2045, 1976), is shown below as Formula (X). 
The compound has a pentacyclic ring system with only one asymmetrical center in ring E with 20(S)-configuration. The pentacyclic ring system includes a pyrrolo [3,4-b]quinoline moiety (rings A, B and C), a conjugated pyridone (ring D), and a six-membered lactone (ring E) with an xcex1-hydroxyl group. Camptothecin was of great interest from the time of its initial isolation due to its noteworthy activity in the mouse leukemia L 1210 system. Earlier data for the antitumor activity of camptothecin were obtained by employing experimentally transplanted malignancies such as leukemia L 1210 in mice, or Walker 256 tumor in rats (Chem. Rev. 23, 385, 1973, Cancer Treat. Rep. 60, 1007, 1967). Subsequent clinical studies showed that this compound was not usable as an anticancer agent in vivo due to its high toxicity. Camptothecin itself is insoluble in water. Therefore, camptothecin was evaluated clinically as a water-soluble sodium carboxylate salt in the early times. This form of camptothecin produced severe toxicity and seemed devoid of anticancer activity (Gottlieb et al, Cancer Chemother. Rep. 54, 461, 1970, and 56, 103, 1972, Muggia et al, Cancer Chemother. Rep. 56, 515, 1972, Moertel et al, Cancer Chemother. Rep. 56, 95, 1972, and Schaeppi et al, Cancer Chemother. Rep. 5:25, 1974). These results caused the discontinuation of phase II trials. Continued evaluation of this agent showed that the sodium carboxylate salt is only 10% as potent as the native camptothecin with the closed lactone ring intact (Wall et al, In International Symposium on Biochemistry And Physiology of The Alkaloids, Mothes et al, eds, Academie-Verlag, Berlin, 77, 1969, Giovanella et al, Cancer res. 51, 3052, 1991). In addition, important parameters for antitumor activity in the camptothecin family have been established (Wall et al, Ann. Rev., Pharmacol. Toxicol. 17, 117, 1977). These results indicate that intact lactone ring E and xcex1-hydroxyl group are essential for antitumor activity.
In 1989, Giovanella et al. found that some of the non-water soluble derivatives of campotothecin have high antitumor activity against xenograft of human tumors (Giovanella et al., Science, 246, 1046, 1989). It has also been shown that administration of camptothecin with closed lactone ring is superior to injections of water-soluble carboxylate salt (Giovanella et al, Cancer Res., 51, 3052, 1991). These findings further confirmed the importance of the intact lactone ring.
Clearly, there is a need to modify 20(S)-camptothecin (xe2x80x9cCPTxe2x80x9d) to enable the lactone form to stay loner in the body while retaining the structural elements (i.e. 20-hydroxyl and lactone ring E) which are essential for its antitumor activity.
Ring opening of CPT leads to much more potent anticancer activity in mice than in humans. In effect, CPT administered intramuscularly (xe2x80x9ci.m.xe2x80x9d), subcutaneously (xe2x80x9cs.c.xe2x80x9d), and intrastomach (xe2x80x9ci.s.xe2x80x9d) has proved to be a very potent anticancer agent against human tumors in mice, i.e., when growing as xenotransplants in nude mice (Giovanella et al, Cancer Res. 51:3052, 1991). However, when tumors were treated with CPT in humans, a lower degree of anticancer activity in humans, than in mice, was exhibited (Stehlin et al., In Camptothecins: New Anticancer Agents, 1995, CRC Press, p. 59-65).
The same phenomenon was observed with other CPT derivatives. In mice, 9-nitrocamptothecin (xe2x80x9c9NCxe2x80x9d) has proven to be 2-3 times more potent than CPT against human tumor xenografts causing the total eradication of all the human malignancies treated (Pantazis et al., Cancer Res. 53:1577, 1993; Pantazis et al., Int. J. Cancer 53:863, 1995).
Pharmacological studies demonstrated that the majority (57%) of the 9NC drug present in the plasma after i.s. administration is in the closed lactone form (FIG. 3). Pharmacological studies on the plasma levels of 9NC after oral administration to Phase I clinical trial patients demonstrate that, on average, only xe2x88x923% of the drug present is in the closed lactone form (FIGS. 4 and 5).
In perfect agreement with such findings, the clinical responses in this group of patients, although higher than those obtained with CPT are still a far cry below the results obtained in mice (32/32 complete tumor regressions in mice versus 2/32 in humans). Clearly, again there is a pressing need for a modification which will slow and delay the lactone ring opening upon its entrance into the blood circulation.
A number of attempts have made to provide more active derivatives of camptothecin, but none of these compounds has been disclosed to be able to delay the opening of the lactone ring E.
Accordingly, it is an object of the present invention to provide new CPT derivatives which are effective antitumor agents, preferably useful for the oral and intramuscular routes of drug administration.
It is another object of the present invention to provide new active CPT derivatives which sustain the opening of the lactone ring E, which makes the antitumor activity last longer than its mother analog, CPT.
It is still another object of the present invention to provide new CPT derivatives which retain significant antitumor activity as does the mother compound, CPT, and have much lower toxicity than its mother compound.
It is still another object of the present invention to provide new CPT derivatives possessing good absorbability in the living body.
It is a further object of the present invention to provide new CPT derivatives which retain the lactone ring E and the 20-hydroxyl group intact, which are important for antitumor activity.
It is still a further object of the present invention to provide a method for preparing CPT derivatives.
Additional objects and advantages of the present invention will be set forth in part in the description which follows, and in part will be apparent from the description, or may be learned by practice of the present invention. The objects and advantages of the present invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.
To achieve the objects and in accordance with the purpose of the present invention, as embodied and broadly described herein, the present invention relates to a compound of formula (I): 
wherein R2 is H or NO2, and R1 is a C1-C4 alkyl group, a C5-C15 alkyl group, a C3-C8 cycloalkyl group, a C2-C15 alkenyl group, or an epoxy group when R2 is H; and R1 is a C1-C15 alkyl group, a C1-C15 alkenyl group, a C3-C5 cycloalkyl group, or an epoxy group when R2 is NO2.
The invention also relates to a method for treating malignant tumors in a mammal and comprises administering an effective amount of one or more of the above compounds.